This invention relates to a process for covalently coupling organic compounds, in particular to a process for covalently linking an olefinic moiety via an organoboron intermediate to other organic compounds. The invention also relates to a process for the preparation of the organoboron intermediates.
Process for forming covalent bonds between olefinic compounds and organic compounds, both inter- and intra-molecular, are of particular importance to the synthetic organic chemist. Many such reactions are known, each requiring its own special reaction conditions, solvents, catalysts, activating groups etc. Some known types of coupling reactions involving olefinic moieties include the Michael reaction and reactions described in the following references: Transition Metals in the Synthesis of Complex Organic Molecules (L. S. Hegedus, University Science Books, 1994, ISBN 0-935702-28-8); Handbook of Palladium Catalysed Organic Reactions (J. Malleron, J. Fiaud and J. Legros, Academic Press, 1997, ISBN 0-12-466615-9); Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7); and N. Miyuara and A. Suzuki, Chem Rev. 1995, 95, 2457-2483.
Catalysts of palladium, its complexes and its salts are well recognised for activation of Cxe2x80x94H bonds towards coupling reactions. In this regard the Heck reaction of an alkene with an aryl or vinyl halide in the presence of palladium derivatives has been the subject of intensive study. However commercial development of the Heck reaction has not progressed as rapidly as could have been expected. Other Group VIII metal catalysts, such as platinum, have also been used to activate such carbon bonds.
The success of the Heck reaction depends to a large extent on the substrates and the reaction conditions. When two xcex2-hydrogens are present in the alkene the reaction generally leads to the formation of the (E)-alkenes which are often contaminated with the corresponding (Z)-alkenes.
Although alkene borates (alkenylborates) can be reacted with a variety of organic molecules to give coupled products via the formation of new carbon-carbon bonds (See for example the references above) the process for the preparation of the alkenylborates by the commonly used hydroboration reaction of alkynes is limited because of the difficulties that are encountered through the lack of regiochemistry and/or chemoselectivity (such as the reduction of a number of different functional groups) (See N. Miyuara and A. Suzuki, Chem Rev. 1995, 95, 2457-2483).
Improved methodologies are thus required for the synthesis of alkene borates.
It has now been found that alkene borates can be synthesised from haloalkenes or pseudo-haloalkenes under mild conditions and in the presence of a range of substituents. This process overcomes or at least alleviates one or more of the limitations encountered in the use of the hydroboration methodology and is fundamentally different in that the starting material is an alkene and not an alkyne. Coupling of the alkenylborates with an organic compound may be achieved in the presence of Group VIII metal catalyst and a suitable base.
Accordingly the invention provides a process for covalently coupling organic compounds which comprises reacting an olefinic compound having a halogen or halogen-like substituent in a vinylic coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base.
In one embodiment this process may be used to prepare a symmetrical product. In this embodiment the coupling proceeds in two steps. In the first step the diboron derivative reacts with an olefinic compound in the presence of the Group VIII metal catalyst and suitable base to form an alkene borate intermediate, this intermediate reacts in the presence of base with remaining olefinic compound. According to this embodiment the covalent coupling comprises a covalent bond between coupling positions of two molecules of olefinic compound.
Preferably the suitable base used to catalyse the reaction with the diboron derivative is also able to catalyse the coupling of the alkene borate intermediate to the remaining olefinic compound. However, if necessary, a stronger base can be added or the reaction mixture can be heated after the formation of the alkene borate intermediate to catalyse or promote the coupling reaction.
The process according to the invention also allows the preparation of unsymmetrical products. Accordingly in another embodiment of the invention there is provided a process for covalently coupling organic compounds which comprises:
reacting an olefinic compound having a halogen or halogen-like substituent at a vinylic coupling position with a diboron derivative in the presence of a Group VIII catalyst and a suitable base to form an alkene borate intermediate, and
reacting the alkene borate intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the olefinic compound is coupled to the organic compound via a direct bond between the respective coupling positions.
The process according to this embodiment allows the preparation of unsymmetrical compounds when the organic compound is different from the olefinic compound, although symmetrical products will be obtained if the organic compound is the same as the olefinic compound.
It is especially convenient to conduct the process in a single pot without isolation of the alkene borate intermediate, however it has been found that the presence of unreacted diboron derivative can interfere with the coupling step, resulting in the formation of unwanted by-products.
Accordingly in another embodiment of the present invention there is provided a process for covalently coupling organic compounds which comprises:
reacting an olefinic compound having a halogen or halogen-like substituent at a vinylic coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an alkene borate intermediate,
adding water or water and a suitable base to decompose excess diboron derivative,
reacting the alkene borate intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base, whereby the olefinic compound is coupled to the organic compound via a direct bond between respective coupling positions.
Preferably the reaction is conducted in a single pot, although it is possible to isolate the alkene borate intermediate prior to the final coupling step. If the reaction is conducted in a single pot it is preferred that the base added to decompose the diboron derivative is suitable for catalysing the coupling reaction. In this case there is no need to add further base with the organic compound in the coupling reaction.
In another embodiment, after formation of the alkene borate intermediate, the coupling of the alkene borate intermediate with the organic compound is achieved by increasing the temperature of the reaction mixture to a temperature sufficient for said coupling reacting to occur. In this embodiment it may not be necessary to add a stronger base to catalyse the coupling reaction.
In cases where there is a need to remove excess diboron derivative but the use of water or water and base is deleterious because of the sensitivity of substituents, etc, or other factors the excess diboron derivative may be decomposed by addition of mild oxidising agents following the formation of the alkene borate intermediate.
Accordingly in a further embodiment there is provided a process for covalently coupling organic compounds which comprises:
reacting an olefinic compound having a halogen or halogen-like substituent at a vinylic coupling position with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an alkene borate intermediate;
adding a mild oxidising agent to decompose excess diboron derivative;
reacting the alkene borate intermediate with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base whereby the olefinic compound is coupled to the organic compound via a direct bond between respective coupling positions.
The mild oxidising agent may be any compound which will break the Bxe2x80x94B bond of the diboron derivative but which is not strong enough to break boronxe2x80x94carbon bonds of the alkene borate intermediate. Suitable mild oxidising agents are N-chlorosuccinimide, dioxygen gas, chloramine-T, chloramine-B, 1-chlorotriazole, 1,3-dichloro-5,5-dimethylhydantoin, trichloroisocyanuric acid and dichloroisocyanuric acid potassium salt.
Oxidants such as hydrogen peroxide, ozone, bromine, t-butyl hydroperoxide, potassium persulphate, sodium hypochlorite and peracids, are too strong for use in this process; use of strong oxidants does not form part of this invention.
The terms xe2x80x9colefinicxe2x80x9d and xe2x80x9colefinic compoundxe2x80x9d as used herein refer to any organic compound having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system. The olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond. Examples of suitable olefinic compounds include but are not limited to ethylene, propylene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, cyclopentene, 1-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, cyclooctene, non-1-ene, non-4-ene, dec-1-ene, dec-3-ene, buta-1,3-diene, penta-1,4-diene, cyclopenta-1,4-diene, hex-1,diene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohepta-1,3,5-triene and cycloocta-1,3,5,7-tetraene, each of which may be optionally substituted. Preferably the straight chain branched or cyclic alkene contains between 2 and 20 carbon atoms.
In one embodiment the olefinic compound is a compound of formula I 
where R1, R2 and R3 are each independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, arylalkyl and heteroarylalkyl (each of which may be optionally substituted), cyano, isocyano, formyl, carboxyl, nitro, halo, alkoxy, alkenoxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitroalkyl, nitroalkenyl, nitroalkynyl, arylamino, diarylamino, dibenzylarnino, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocycloxy, arylsulphenyl, carboalkoxy, carboaryloxy, alkylthio, benzylthio, acylthio, sulphonamide, sulfanyl, sulfo, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sulfamyl, phosphorous containing groups (including phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphone (including phosphonato) and hydrohydroxyphosphoryl), guanidinyl, duanidino, ureido and ureylene, and X is a halogen or halogen-like substituent.
As used herein the term xe2x80x9corganic compound having a halogen or halogen-like substituent at a coupling positionxe2x80x9d refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position where coupling to the olefinic compound is desired. The organic compound may be aliphatic, olefinic, allylic, acetylenic, aromatic, polymeric or dendritic. The compound may be an olefinic compound as defined above or part of such an olefinic compound. The organic compound may have one or more, preferably between 1 and 6, halogen or halogen-like substituents at coupling positions.
The terms xe2x80x9caromaticxe2x80x9d and xe2x80x9caromatic compound(s)xe2x80x9d as used herein refers to any compound or moiety which includes or consists of one or more aromatic or pseudoaromatic rings. The rings may be carbocyclic or heterocyclic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetrahydronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The terms xe2x80x9caromaticxe2x80x9d and xe2x80x9caromatic compound(s)xe2x80x9d includes molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic or pseudoaromatic rings. The term xe2x80x9cpseudoaromaticxe2x80x9d refers to a ring system which is not strictly aromatic, but which is stablized by means of delocalization of xcfx80 electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
The term xe2x80x9ccoupling positionxe2x80x9d as used herein refers to a position on an organic compound at which coupling to another organic compound is desired. A coupling position on a carbon atom which is part of an olefinic carbon to carbon bond is also referred to as a xe2x80x9cvinylic coupling positionxe2x80x9d. Each olefinic compound or organic compound may have one or more, preferably between 1 and 6, coupling positions.
In this specification xe2x80x9coptionally substitutedxe2x80x9d means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimine, alkenylimine, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups, alkoxysilyl, silyl, alkylsilyl, alkylalkoxysilyl, phenoxysilyl, alkylphenoxysilyl, alkoxyphenoxy silyl and arylphenoxy silyl.
The olefinic compound must include at least one halogen or halogen-like substituent at a vinylic coupling position to enable reaction with the diboron derivative. Similarly the organic compound must have at least one halogen or halogen-like substituent at a coupling position to enable reaction with the alkene borate intermediate. Preferred halogen substituents include I, Br and Cl. The reactivity of chloro substituted aromatic ring compounds can be increased by selection of appropriate ligands on the Group VIII metal catalyst. The terms xe2x80x9chalogen-like substituentxe2x80x9d and xe2x80x9cpseudo-halidexe2x80x9d refer to any substituent which, if present, may undergo substitution with a diboron derivative in the presence of a Group VIII metal catalyst and base to give an alkene borate intermediate, or if present on an organic compound may undergo substitution with an alkene borate intermediate to give a coupled product. Examples of halogen-like substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7).
The process according to the present invention is especially suitable for coupling olefinic compounds containing substituents which are reactive with organometallic compounds, such as Grignard reagents or alkyl lithiums, therefore unsuitable for reacting using standard Grignard methodology unless these substituents are first protected. One such class of reactive substituents are the active hydrogen containing substituents. The term xe2x80x9cactive hydrogen containing substituentxe2x80x9d as used herein refers to a substituent which contains a reactive hydrogen atom. Examples of such substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene. Of these substituents it is particularly surprising that the reaction can be conducted with hydroxy and amino substituents in view of their high reactivity. Carboxyl, sulfo and the like (i.e. acidic) substituents may require additional base. Other reactive substituents include trimethylsilyl.
In the above definitions, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-,2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkoxyxe2x80x9d denotes straight chain or branched alkoxy, preferably C1-20 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.
The term xe2x80x9calkenylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2-20 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
The term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkyne including those structurally similar to the alkyl and cycloalkyl groups as previously defined, preferably C2-20 alkynyl. Examples of alkynyl include ethynyl, 2-propynyl and 2- or 3-butynyl.
The term xe2x80x9cacylxe2x80x9d either alone or in compound words such as xe2x80x9cacyloxyxe2x80x9d, xe2x80x9cacylthioxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cdiacylaminoxe2x80x9d denotes carbarnoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1-20 acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl; aralkenoyl such as phenylalkenoyl (e. g. phenylpropenoyl, phenylbutenoyl, phenyimethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.
The terms xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocyclxe2x80x9d as used herein on their own or as part of a term such as xe2x80x9cheterocyclicalkenoylxe2x80x9d, heterocycloxyxe2x80x9d or xe2x80x9chaloheterocyclylxe2x80x9d refer to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, O and P and which may be optionally substituted. Preferably the rings or ring systems have 3 to 20 carbon atoms. The rings or ring systems may be selected from those described above in relation to the definition of xe2x80x9caromatic compound(s)xe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein on its own or as part of a group such as xe2x80x9chaloarylxe2x80x9d and xe2x80x9caryloxycarbonylxe2x80x9d refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, optionally together with one or more heteroatoms. Preferably the rings or ring systems have between 3 and 20 carbon atoms. The rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of xe2x80x9caromatic compound(s)xe2x80x9d.
The diboron derivative may be an ester or other stable derivative of diboronic acid. Examples of suitable esters include those of the formula (RO)2Bxe2x80x94B(RO)2 where R is optionally substituted alkyl or optionally substituted aryl or xe2x80x94B(OR)2 represents a cyclic group of formula 
where Rxe2x80x2 is optionally substituted alkylene, arylene or other divalent group comprising linked aliphatic or aromatic moieties. Preferred diboron derivatives include bis(pinacolato)diboron (the pinacol ester of diboronic acid), bis(ethanediolato)diboron, bis(n-propanediolato)diboron and bis(neopentanediolato)diboron. Some of the diboron derivatives will be more readily amenable to subsequent hydrolysis than others and may allow for the use of milder reaction conditions. Furthermore, judicious choice of the diboron derivative used may facilitate control over the reaction products formed. The diboron ester derivatives may be made following the method of Brotherton et al. [R. J. Brotherton, A. L. McCloskey, L. L. Peterson and H. Steinberg, J. Amer. Chem. Soc. 82, 6242 (196); R. J. Brotherton, A. L. McCloskey, J. L. Boone and H. M. Manasevit, J. Amer. Chem. Soc. 82, 6245 (1960)]. In this process B(NMe2)3, obtained by reaction of BCl3 with NHME2, is converted to BrB(NMe2)2 by reaction with a stoichiometric amount of BBr3. Reduction in refluxing toluene with sodium metal gives the diboron compound [B(NMe2)2]2 which, after purification by distillation, can be reacted with the alcohol (for example, pinacol) in the presence of a stoichiometric amount of HCl to give the desired ester product. Bis(neopentanediolato)diboron is described by Nguyen et al [Nguyen, P., Lesley, G., Taylor, N. J., Marder, T. B., Pickett, N/L/, Clegg, W., Elsegood, M. R. J., and Norman, N. C., Inorganic Chem. 1994, 33, 4623-24]. Other methods for the preparation of the diboron derivatives would be known to those in the art.
The term xe2x80x9cGroup VIII metal catalystxe2x80x9d as used herein refers to a catalyst comprising a metal of Group 8 of the periodic table described in Chemical and Engineering News, 63(5), 27, 1985. Examples of such metals include Ni, Pt and Pd. Preferably the catalyst is a palladium catalyst as described below, although analogous catalysts of other Group VIII metals may also be used. Examples of suitable Ni catalysts include nickel black, Raney nickel, nickel on carbon and nickel clusters or a nickel complex. Examples of suitable Pt catalysts include platinum black, platinum on carbon and platinum clusters or a platinum complex. The Group VIII metal catalyst may additionally include other metals.
The palladium catalyst may be a palladium complex. Examples of suitable palladium catalysts include but are not limited to PdCl2, Pd(OAc)2, PdCl2(dppf)CH2Cl2, Pd(PPh3)4 and related catalysts which are complexes of phosphine ligands, (such as (Ph2P(CH2)PPh2) where n is 2 to 4, P(o-tolyl)3, P(i-Pr)3, P(cyclohexyl)3, P(o-MeOPh)3, P(p-MeOPh)3, dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth), phosphite ligands (such as P(OEt)3, P(O-p-tolyl)3, P(O-o-tolyl)3 and P(O-iPr)3) and other suitable ligands including those containing P and/or N atoms for co-ordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2xe2x80x2-bipyridyl, alkyl substituted 2,2xe2x80x2-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands. The palladium catalysts include palladium and palladium complexes supported or tethered on solid supports, such as palladium on carbon, as well as palladium black, palladium clusters, palladium clusters containing other metals, and palladium in porous glass as described in J. Li, A. W-H. Mau and C. R. Strauss, Chemical Communications, 1997, p1275. The same or different palladium catalysts may be used to catalyse different steps in the process. The palladium catalyst may also be selected from those described in U.S. Pat. No. 5,686,608. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk.
The process may be performed in any suitable solvent or solvent mixture. Examples of such solvents include lower alcohols, and their esters with the lower aliphatic carboxylic acids, cyclic and the lower secondary and tertiary amines, amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, DMSO, aromatic hydrocarbons, nitromethane, acetonitrile, benzonitrile, ethers, polyethers, cyclic ethers, lower aromatic ethers, and mixtures thereof, including mixtures with other solvents.
Preferred solvents include methanol, ethanol, isopropanol, DMSO, DMF, dioxane, DME, diethyl ether, THF or mixtures thereof with other solvents. Exclusion of water from the solvents is generally not essential and in some cases the presence of water is preferred. The addition of further diboron derivative may be useful when the solvents are not anhydrous.
The temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc. The temperature of the reaction will generally be in the range of xe2x88x92100 to 250xc2x0 C. In a preferred embodiment the process is performed at a temperature between 0 and 120xc2x0 C, more preferably between 0 and 80xc2x0 C., and most preferably between 15 and 40xc2x0 C.
The term xe2x80x9csuitable basexe2x80x9d as used herein refers to a basic compound which, when present in the reaction mixture, is capable of catalysing, promoting or assisting reaction between reactants. The base may be suitable for catalysing a single step, or more than one step, depending on the desired outcome of the reaction. For example a base may be chosen which catalyses reaction between the olefinic compound and the diboron derivative, but which is not strong enough under the conditions used in the reaction to catalyse further reaction of the alkene borate intermediate with additional olefinic compound or other organic compound. In this case water or water and a stronger base may be added to decompose excess diboron derivative, and which may also catalyse reaction of the alkene borate intermediate with the organic compound. It is also preferable that a base is chosen which is soluble in the solvent to which it is added. Examples of bases which are suitable for catalysing the reaction of the olefinic compound with the diboron derivative include, aryl and alkyl carboxylates (for example potassium acetate), fluorides, hydroxides and carbonates of Li, Na, K, Rb, Cs, ammonium, alkylammonium, Mg, Ca, and Ba; phosphates and arylphosphates of Li, Na, K, Rb and Cs; phosphate esters (eg. C6H5OP(O)(ONa)2) of Li, Na, K, Rb, Cs, ammonium and alkylammonium; phenoxides of Li, Na, K, Rb and Cs; alkoxides of Li, Na, K, Rb and Cs; and thallium hydroxide. Some of these bases may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammnonium salts or the crown ethers.
Examples of bases suitable for catalysing reaction of the olefinic compounds with the diboron derivative, without generally catalysing the further reaction of the alkene borate intermediate, include aryl and alkyl carboxylates, fluorides, and phosphates of Li, Na, K, Rb, Cs, ammonium and alkylammonium. Depending upon the reaction temperature stronger bases, such as carbonates, may be used.
Examples of bases suitable for decomposing excess diboron derivative and/or catalysing reaction of the alkene borate intermediate with the organic compound include the stronger bases listed above, including cesium carbonate, potassium carbonate, potassium phosphate and alkali metal hydroxides.
As used herein the term xe2x80x9calkene borate intermediatexe2x80x9d refers to the product of the Group VIII metal base catalysed reaction between an olefinic compound having a halogen or halogen-like substituent at a vinylic coupling position and a diboron derivative, the product including a carbon- to -boron bond at the coupling position.
In another aspect of the invention there is provided a process for preparing an alkene borate intermediate comprising reacting a diboron derivative with an olefinic compound having a halogen or halogen-like substituent and an active hydrogen containing substituent in the presence of a Group VIII metal catalyst and a suitable base.
In a further aspect of the invention there is provided a process for preparing an alkene borate intermediate, comprising reacting a diboron derivative with an olefinic compound having a halogen or halogen-like substituent in a protic solvent in the presence of a Group VIII metal catalyst and a suitable base.
A first step in the purification of the alkene borate intermediate so formed may be the decomposition of any excess diboron derivative by the use of water, water and suitable base, or by the use of a mild oxidising agent.
In a further aspect of the invention there is provided a process for the preparation of an olefinic boronic acid by hydrolysing the alkene borate intermediate as hereinbefore described using established procedures. The ease of hydrolysis is a function of the diboronic ester used. Some alkene borate intermediates are more amenable to hydrolysis than those derived from bis(pinacolato)diboron. This method only relates to alkene borate intermediates which are boronic esters.
Some of the alkene borate intermediates and olefinic boronic acids are novel and represent a further aspect of the present invention. Examples of such novel alkene borate intermediates which may be prepared according to the present invention are listed in Table 2, while some known alkene borate intermediates prepared in accordance with the present invention are listed in Table 1.
The term xe2x80x9clinking groupxe2x80x9d as used herein refers to any chain of atoms linking one aryl group to another. Examples of linking groups include polymer chains, optionally substituted alkylene group and any other suitable divalent group.
The process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries. Thus a suitable organic compound having a halogen or halogen-like substituent at a coupling position which is chemically linked to a polymer surface may be reacted with an alkene borate intermediate in the presence of a Group VIII metal catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface. The process is also possible using the alternative strategy of reacting an olefinic compound having a halogen or halogen-like substituent linked to a polymer surface with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an alkene intermediate chemically linked to the polymer surface. This intermediate may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst and a suitable base to prepare the coupled product chemically linked to the polymer. Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer.
It is also possible to prepare polymers by reaction of olefinic compounds having more than one halogen or halogen-like substituent in a vinylic coupling position. Such olefinic compounds may be reacted with a diboron derivative in the presence of a Group VIII metal catalyst and a suitable base to form an alkene borate intermediate having more than one boron functionality. These intermediates may be reacted with organic compounds having more than one halogen or halogen-like substituent to form a polymer. If the olefinic compound has three or more halogen or halogen-like substituents which react with the diboron derivative then it is possible to prepare dendritic molecules in accordance with the process of the present invention.
The olefinic compound and the organic compound may be separate molecules, or may be linked together such that the alkene borate intermediate formed after reaction with the diboron derivative is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction. Similarly the process according to the invention allows intramolecular linking to occur between double bonds located in different parts of a molecule, provided each double bond has a vinylic halogen or halogen-like substituent.
The process according to the invention is also useful for the preparation of reactive intermediates which, after coupling, take part in further reactions or rearrangements. An example of such an intermediate is one formed by reaction of an ether containing vinylic halide with one of R1, R2 or R3 (formula I) being xe2x80x94OR with a diboron derivative. The subsequent coupling of the resulting alkene borate intermediate with an organic compound gives a ketone on hydrolysis of the enol ether.
The process according to the present invention provides an alternative method for coupling olefinic moieties to organic compounds. The process allows the use of mild conditions and avoids the use of expensive, difficult to handle and/or toxic reagents and solvents. In this regard boron and boron compounds are generally non-toxic. The reactions may also be performed in relatively cheap solvents such as methanol and ethanol and, in view of the improved control over the reaction steps, it is envisaged that it would be possible to perform the reactions on an industrial scale. In view of the mild reaction conditions it is also possible to perform the coupling without the need to protect most reactive substituents.
The following examples are provided to illustrate preferred embodiments of the invention.
However it is to be understood that the following description is not to supersede the generality of the invention previously described.